1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXP reductoisomerase or IspC)
EC 1.1.1.267 - 1-deoxy-D-xylulose-5-phosphate reductoisomerase
TDR Targets lists it in: M. leprai, P falciparum, P. vivax, M. tuberculosis, W. endosymbiont of Brugia Malayi
Also a Francisella tularensis target http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0008288
PDB? - yes to the -20 at least
- only 38% Identity though according to PlasmoDB
Paste amino acid sequence to PDB in Advanced Search >> Sequence Features >> Sequence (BLAST/FASTA/PSI-BLAST) >>
E Cutoff: 1 >> 33 structures
Goble Paper - Plasmodium falciparum 3-D model
Downloaded: Protein Pept Lett. 2010 Jan;17(1):109-20.
The malarial drug target Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR): development of a 3-D model for identification of novel, structural and functional features and for inhibitor screening.
Biomedical Biotechnology Research Unit, Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, Grahamstown 6140, South Africa.
Abstract
A three-dimensional model of the malarial drug target protein PfDXR was generated, and validated using structure-checking programs and protein docking studies. Structural and functional features unique to PfDXR were identified using the model and comparative sequence analyses with apicomplexan and non-apicomplexan DXR proteins. Furthermore, we have used the model to develop an efficient approach to screen for potential tool compounds for use in the rational design of novel DXR inhibitors.
J Med Chem. 2011 Jul 14;54(13):4721-34. Epub 2011 Jun 2.
Inhibition of 1-Deoxy-d-Xylulose-5-Phosphate Reductoisomerase by Lipophilic Phosphonates: SAR, QSAR, and Crystallographic Studies.
Department of Pharmacology and ‡Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine , 1 Baylor Plaza, Houston, Texas 77030, United States.
Abstract
1-Deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) is a novel target for developing new antibacterial (including antituberculosis) and antimalaria drugs. Forty-one lipophilic phosphonates, representing a new class of DXR inhibitors, were synthesized, among which 5-phenylpyridin-2-ylmethylphosphonic acid possesses the most activity against E. coli DXR (EcDXR) with a K(i) of 420 nM. Structure-activity relationships (SAR) are discussed, which can be rationalized using our EcDXR:inhibitor structures, and a predictive quantitative SAR (QSAR) model is also developed. Since inhibition studies of DXR from Mycobacterium tuberculosis (MtDXR) have not been performed well, 48 EcDXR inhibitors with a broad chemical diversity were found, however, to generally exhibit considerably reduced activity against MtDXR. The crystal structure of a MtDXR:inhibitor complex reveals the flexible loop containing the residues 198-208 has no strong interactions with the 3,4-dichlorophenyl group of the inhibitor, representing a structural basis for the reduced activity. Overall, these results provide implications in the future design and development of potent DXR inhibitors.
Department of Pharmaceutical Sciences, College of Pharmacy, Pharmacy Building, Room 203, Oregon State University, Corvallis 97331-3507, USA. phil.proteau@oregonstate.edu
Abstract
The methylerythritol phosphate pathway to isoprenoids, an alternate biosynthetic route present in many bacteria, algae, plants, and the malarial parasite Plasmodium falciparum, has become an attractive target for the development of new antimalarial and antibacterial compounds. The second enzyme in this pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR; EC 1.1.1.267), has been shown to be the molecular target for fosmidomycin, a promising antimalarial drug. This enzyme converts 1-deoxy-D-xylulose 5-phosphate (DXP) into the branched compound 2-C-methyl-D-erythritol 4-phosphate (MEP). The transformation of DXP into MEP requires an isomerization, followed by a NADPH-dependent reduction. The discovery of DXR, its subsequent characterization, and the identification of inhibitors will be presented.
Current inhibitor: Fosmidomycin Binding DB shows 1 hit:
Sigma product # F8682 5MG = $136
Fosmidomycin is an inhibitor of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) (MEP synthase): an antimalarial compound. 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is an enzyme involved in the first step in the nonmevalonate pathway for isoprenoid biosynthesis in Gram-negative, Gram-positive bacteria, plants, and the parasite causing the most virulent form of malaria, Plasmodium falciparum (Mammals produce isoprenoids via the mevalonate pathway).
EC 1.1.1.267 - 1-deoxy-D-xylulose-5-phosphate reductoisomerase
TDR Targets lists it in: M. leprai, P falciparum, P. vivax, M. tuberculosis, W. endosymbiont of Brugia Malayi
Also a Francisella tularensis target
http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0008288
(PlasmoDB - essential)
Essentiality: tdrtargets.org
http://tdrtargets.org/targets/view?gene_name=PF14_0641
NCBI Gene:
http://www.ncbi.nlm.nih.gov/gene/812223
Plasmodium falciparans - Malaria
http://plasmodb.org/plasmo/showRecord.do?name=GeneRecordClasses.GeneRecordClass&source_id=PF14_0641&project_id=PlasmoDB
http://tdrtargets.org/targets/view?gene_name=PF14_0641
PDB? - yes to the -20 at least
- only 38% Identity though according to PlasmoDB
Paste amino acid sequence to PDB in Advanced Search >> Sequence Features >> Sequence (BLAST/FASTA/PSI-BLAST) >>
E Cutoff: 1 >> 33 structures
AA Seq:
MKKYIYIYFFFITITINDLVINNTSKCVSIERRKNNAYINYGIGYNGPDNKITKSRRCKR
IKLCKKDLIDIGAIKKPINVAIFGSTGSIGTNALNIIRECNKIENVFNVKALYVNKSVNE
LYEQAREFLPEYLCIHDKSVYEELKELVKNIKDYKPIILCGDEGMKEICSSNSIDKIVIG
IDSFQGLYSTMYAIMNNKIVALANKESIVSAGFFLKKLLNIHKNAKIIPVDSEHSAIFQC
LDNNKVLKTKCLQDNFSKINNINKIFLCSSGGPFQNLTMDELKNVTSENALKHPKWKMGK
KITIDSATMMNKGLEVIETHFLFDVDYNDIEVIVHKECIIHSCVEFIDKSVISQMYYPDM
QIPILYSLTWPDRIKTNLKPLDLAQVSTLTFHKPSLEHFPCIKLAYQAGIKGNFYPTVLN
ASNEIANNLFLNNKIKYFDISSIISQVLESFNSQKVSENSEDLMKQILQIHSWAKDKATD
IYNKHNSS
AA Seq of PDB entry 1R0K (from Zymomonas mobilis - closest hit on search in PDB)
Score = 269 bits (688), Expect = 1e-76, Method: Compositional matrix adjust. Identities = 141/385 (37%), Positives = 219/385 (57%), Gaps = 23/385 (6%)
Henriksson Paper - tuberculosis structures
Goble Paper - Plasmodium falciparum 3-D model
Downloaded:
Protein Pept Lett. 2010 Jan;17(1):109-20.
The malarial drug target Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR): development of a 3-D model for identification of novel, structural and functional features and for inhibitor screening.
Goble JL, Adendorff MR, de Beer TA, Stephens LL, Blatch GL.Source
Biomedical Biotechnology Research Unit, Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, Grahamstown 6140, South Africa.Abstract
A three-dimensional model of the malarial drug target protein PfDXR was generated, and validated using structure-checking programs and protein docking studies. Structural and functional features unique to PfDXR were identified using the model and comparative sequence analyses with apicomplexan and non-apicomplexan DXR proteins. Furthermore, we have used the model to develop an efficient approach to screen for potential tool compounds for use in the rational design of novel DXR inhibitors.J Med Chem. 2011 Jul 14;54(13):4721-34. Epub 2011 Jun 2.
Inhibition of 1-Deoxy-d-Xylulose-5-Phosphate Reductoisomerase by Lipophilic Phosphonates: SAR, QSAR, and Crystallographic Studies.
Deng L, Diao J, Chen P, Pujari V, Yao Y, Cheng G, Crick DC, Prasad BV, Song Y.Source
Department of Pharmacology and ‡Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine , 1 Baylor Plaza, Houston, Texas 77030, United States.Abstract
1-Deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) is a novel target for developing new antibacterial (including antituberculosis) and antimalaria drugs. Forty-one lipophilic phosphonates, representing a new class of DXR inhibitors, were synthesized, among which 5-phenylpyridin-2-ylmethylphosphonic acid possesses the most activity against E. coli DXR (EcDXR) with a K(i) of 420 nM. Structure-activity relationships (SAR) are discussed, which can be rationalized using our EcDXR:inhibitor structures, and a predictive quantitative SAR (QSAR) model is also developed. Since inhibition studies of DXR from Mycobacterium tuberculosis (MtDXR) have not been performed well, 48 EcDXR inhibitors with a broad chemical diversity were found, however, to generally exhibit considerably reduced activity against MtDXR. The crystal structure of a MtDXR:inhibitor complex reveals the flexible loop containing the residues 198-208 has no strong interactions with the 3,4-dichlorophenyl group of the inhibitor, representing a structural basis for the reduced activity. Overall, these results provide implications in the future design and development of potent DXR inhibitors.Bioorg Chem. 2004 Dec;32(6):483-93.
1-Deoxy-D-xylulose 5-phosphate reductoisomerase: an overview.
Proteau PJ.Source
Department of Pharmaceutical Sciences, College of Pharmacy, Pharmacy Building, Room 203, Oregon State University, Corvallis 97331-3507, USA. phil.proteau@oregonstate.eduAbstract
The methylerythritol phosphate pathway to isoprenoids, an alternate biosynthetic route present in many bacteria, algae, plants, and the malarial parasite Plasmodium falciparum, has become an attractive target for the development of new antimalarial and antibacterial compounds. The second enzyme in this pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR; EC 1.1.1.267), has been shown to be the molecular target for fosmidomycin, a promising antimalarial drug. This enzyme converts 1-deoxy-D-xylulose 5-phosphate (DXP) into the branched compound 2-C-methyl-D-erythritol 4-phosphate (MEP). The transformation of DXP into MEP requires an isomerization, followed by a NADPH-dependent reduction. The discovery of DXR, its subsequent characterization, and the identification of inhibitors will be presented.Current inhibitor: Fosmidomycin
Binding DB shows 1 hit:
Sigma product # F8682 5MG = $136
Fosmidomycin is an inhibitor of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) (MEP synthase): an antimalarial compound. 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is an enzyme involved in the first step in the nonmevalonate pathway for isoprenoid biosynthesis in Gram-negative, Gram-positive bacteria, plants, and the parasite causing the most virulent form of malaria, Plasmodium falciparum (Mammals produce isoprenoids via the mevalonate pathway).
Enzyme Assay? - maybe NADPH absorbance?
from tdrtargets.org
Assay: Assay for Glyoxylate Reductase (1.1.1.26 ); Source: Sigma-Aldrich
http://www.sigmaaldrich.com/etc/medialib/docs/Sigma/General_Information/glyoxylate_reductase.Par.0001.File.dat/glyoxylate_reductase.pdf
Listed substrate - but may not be good.
Sodium glyoxylate monohydrate
G-4502 $56 for 1gram
Better is 1-deoxy-D-xylulose 5-phosphate (214.11 Mol Weight, Product # 13368-1MG = $65
DXP (Echelon Biosciences, Salt Lake City, UT)
http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0008288